Intellectual disability
Gene: TFE3 Red List (low evidence)Green List (high evidence)
[This gene was present in the ID panel with red rating, though with no reviews].
7 unrelated individuals with de novo TFE3 pathogenic variants have been reported in the following studies:
[1] Villegas et al (2019 - PMID: 30595499) - Lysosomal Signaling Licenses Embryonic Stem Cell Differentiation via Inactivation of Tfe3 [5 individuals]
[2] Diaz et al (2019 - PMID: 31833172) - TFE3-associated neurodevelopmental disorder: A distinct recognizable syndrome [2 additional individuals]
Overlapping features observed in almost all included DD and severe ID (7/7), coarse facial features (6/7) as well as blaschkoid pigmentary mosaicism (6/7). Epilepsy was reported in 5/7. Variable other features observed in some/few included (by decreasing order of frequency): hypotonia, developmental regression, obesity, hand stereotypies, hepatomegaly, umbilical hernia, ASD, recurrent otitis media, hypoglycemia, etc.
TFE3 encodes transcription factor for immunoglobulin heavy-chain enhancer 3. The gene lies on Xp11.23.
All individuals reported to date have been found to harbor de novo variants affecting exons 3 or 4. Six different missense variants have been reported. A suspected ectopic nuclear gain-of-function effect has been proposed in Ref1. One additional similarly affected individual harbored a canonical splice site variant (NM_006521.4:c.780+1G>A in intron 4) predicted to lead to in-frame skipping of exon 4 (Ref2).
6/7 affected individuals were females. Random X-chromosome inactivation (XCI) was shown for an individual with blaschkoid pigmentary mosaicism. It has been commented and shown that the (single) female without BPM had skewed XCI (Ref1).
A single male was also affected. This individual harbored a de novo mosaic variant (65% in blood) (Ref1).
Previous investigations included among others:
- metabolic work-up in some individuals (Refs1/2), also for suspected lysosomal disorders (due to coarse facial features, hepatomegaly, hypoglycemia, etc)
- conventional karyotype in some cases (for one individual a mosaic t(X;11) with Xp22.3 microdeletion was demonstrated in Ref1, but this did not contain genes for ID/epilepsy reason why WES was subsequently pursued)
- SNP-CMA (skin & blood or skin only - for the 2 individuals in Ref2)
- For individuals from Ref2 variable IKBKG genetic testing, testing for Angelmann/Beckwith-Wiedemann syndrome, ID/epilepsy/ASD gene panel testing was carried out.
Exome sequencing in some cases in Ref2 revealed additional de novo variants in other genes not thought to contribute to the phenotype due to the inheritance mode (AR with absence of other variant in trans) or due to in silico predictions predicting a tolerated/benign effect for the respective variant(s) (eg. for NCOR1).
To the best of my understanding (?) and better summarized by VanHook AM (2019 - DOI: 10.1126/scisignal.aax0926 - https://stke.sciencemag.org/content/12/570/eaax0926 ):
Sequestering of Tfe3 in the cytoplasm (through recruitment to the lysosomal membrane) prevents its role as transcription factor in the nucleus. Mutations preventing its recruitment to lysosomes, prevent cytoplasmic sequestration, enabling Tfe3 to enter the nucleus and in turn affect (/block) stem cell differentiation. Exons 3 and 4 are suggested to form a structure important for cytoplasmic Tfe3 inactivation. Villegas et al studied Tfe3 KO embryonic stem cells (ESCs) expressing murine alleles (Q118P and P185L) corresponding to mutations observed in affected individuals (Q119P/P186L). The variants were shown to affect Tfe3 localization (/induce nuclear localization) and prevent spontaneous differentiation of ESCs into neural progenitors. Signalling pathways and functional effects (as proposed by Villegas et al) are summarized in the reference above.Created: 27 Dec 2019, 10:49 p.m. | Last Modified: 27 Dec 2019, 10:49 p.m.
Panel Version: 3.0
Mode of inheritance
Other
Phenotypes
Global developmental delay; Intellectual disability; Abnormality of skin pigmentation; Coarse facial features; Seizures
Publications
Mode of pathogenicity
Other
gene: TFE3 was added gene: TFE3 was added to Intellectual disability. Sources: Victorian Clinical Genetics Services Mode of inheritance for gene: TFE3 was set to
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at [email protected]
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.